U.S. patent number 5,120,713 [Application Number 07/580,686] was granted by the patent office on 1992-06-09 for treatment of obesity with an alpha-2-adrenergic agonist and a growth hormone releasing peptide.
This patent grant is currently assigned to Applied Research Systems ARS Holding N.V.. Invention is credited to Jesus D. Mugica.
United States Patent |
5,120,713 |
Mugica |
June 9, 1992 |
Treatment of obesity with an alpha-2-adrenergic agonist and a
growth hormone releasing peptide
Abstract
Obese patients may be effectively treated by cojointly
administering an alpha-2-adrenergic agonist, such as clonidine, and
a growth hormone releasing peptide, such as GHRH, to restore or
substantially enhance growth hormone release in such patients.
Inventors: |
Mugica; Jesus D. (La Coruna,
ES) |
Assignee: |
Applied Research Systems ARS
Holding N.V. (Curacao, AN)
|
Family
ID: |
24322121 |
Appl.
No.: |
07/580,686 |
Filed: |
September 10, 1990 |
Current U.S.
Class: |
514/4.8;
514/20.6; 514/11.3; 514/401 |
Current CPC
Class: |
A61P
3/04 (20180101); A61P 25/02 (20180101); A61K
38/25 (20130101); A61K 38/25 (20130101); A61K
31/415 (20130101); A61K 38/25 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
38/25 (20060101); A61K 037/00 () |
Field of
Search: |
;514/12,16,17,401 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Williams, N. Engl. J. Med. 311:1403, 1984. .
Kopelman, Clin. Endocrinol. 23:87, 1985. .
Kopelman, Clin. Endocrinol. 24:157, 1986. .
Loche, Clin. Endocrinol. 27:145, 1987. .
Cordido, J. Clin. Endocrinol. Metab., 68:290, 1989. .
Ghigo, J. Endocrinol Invest. 12:99, 1989. .
Davis, J. Clin. Endocrinol. Metab. 65:1248, 1987. .
Chatterjee, J. Endocrinol. 116:R1-R2, 1988. .
Reiter, J. Pediat. Endocrinol. 3:21, 1988. .
Arce, Neuroendocrinology 52/S1/90:119, 1990, Poster 3.50 of 2nd
Int'l Cong. of Neuroendocrinology held Jun. 24-29, 1990. .
Ghigo, "Effects of the Enhancement of the Cholinergic Activity on
Growth Hormone Secretion in Children: Clinical Implications",
Recent Advances in Basic and Clinical Neuroendocrinology (eds.
Casanueva and Dieguez), pp. 241-251, 1989, Excerpta Medica,
Amsterdam. .
Cordido et al., Chem. Abstracts 113:453 (Jul. 1990), abstract
21676S..
|
Primary Examiner: Cashion, Jr.; Merrell C.
Assistant Examiner: Koh; Choon
Attorney, Agent or Firm: Williams; Stephan P.
Claims
What is claimed is:
1. A method of inducing growth hormone secretion in an obese
patient which comprises administering cojointly to said patient an
effective amount of an alpha-2-adrenergic agonist and a growth
hormone releasing peptide.
2. The method of claim 1 wherein said alpha-2-adrenergic agonist is
clonidine.
3. The method of claim 2 wherein said clonidine is administered
from 0 to about 120 minutes prior to said growth hormone releasing
peptide.
4. The method of claim 3 wherein said growth hormone releasing
peptide is GRF 1-44, GRF 1-40, GRF 1-37, or GRF 1-29.
5. The method of claim 2 wherein said clonidine is administered in
an amount of about 100 to about 300 micrograms/m.sup.2.
6. The method of claim 4 wherein said growth hormone releasing
peptide is administered in an amount of about 1 ug/kg i.v. or about
10 ug/kg s.c..
7. The method of claim 4 wherein said clonidine is administered in
an amount of about 150 micrograms/m.sup.2.
8. The method of claim 1 wherein said growth hormone releasing
peptide has the formula AA.sub.1 -His-AA.sub.3
-Ala-Trp-D-Phe-Lys-NH.sub.2 wherein AA.sub.1 is H or Ala and
AA.sub.3 is D-Trp or D-.beta.-Nal.
9. A method of treating obesity which comprises administering to a
patient with this condition an alpha-2-adrenergic agonist cojointly
with a growth hormone releasing peptide in an amount effective to
induce growth hormone secretion in said patient.
10. The method of claim 9 wherein said alpha-2-adrenergic agonist
is clonidine.
11. The method of claim 10 wherein said clonidine is administered
from 0 to about 120 minutes prior to said growth hormone releasing
peptide.
12. The method of claim 11 wherein said growth hormone releasing
peptide is GRF 1-44, GRF 1-40, GRF 1-37, or GRF 1-29.
13. The method of claim 10 wherein said clonidine is administered
in an amount of about 100 to about 300 micrograms/m.sup.2.
14. The method of claim 12 wherein said growth hormone releasing
peptide is administered in an amount of about 1 ug/kg i.v. or about
10 ug/kg s.c..
15. The method of claim 12 wherein said clonidine is administered
in an amount of about 150 micrograms/m.sub.2.
16. The method of claim 9 which additionally comprises placing said
patient on a hypocaloric diet.
17. The method of claim 9 wherein said growth hormone releasing
peptide has the formula AA.sub.1 -His-AA.sub.3
-Ala-Trp-D-Phe-Lys-NH.sub.2 wherein AA.sub.1 is H or Ala and
AA.sub.3 is D-Trp or D-.beta.-Nal.
Description
BACKGROUND OF THE INVENTION
This invention relates to the treatment of obesity with an
alpha-2-adrenergic agonist and a growth hormone releasing peptide
to induce growth hormone secretion in a patient with this
condition.
It is generally known that obese patients have impaired growth
hormone (GH) release, both in basal conditions and in response to a
number of stimuli, including growth hormone releasing hormone
(GHRH, also identified as GRF) (1,2,3,4). This has been postulated
to be the result of a hypothalamic disorder (3), leading to a
chronic state of somatostatin hypersecretion (5).
It is also known that administering to a normal patient an agent
that interferes with the hypothalamic release of somatostatin will
enhance growth hormone release. This effect has been shown for
clonidine, an alpha-2-adrenergic agonist, and pyridostigmine, a
cholinergic agonist, although the mechanism of action is different
for each drug (6). Likewise, galanin has been shown to potentiate
GHRH induced GH secretion in normal subjects (7) via the
cholinergic pathways (8). It has also been recently shown that
treatment of obese patients with the cholinergic agonist
pyridostigmine will moderately restore the growth hormone
responsiveness to GHRH administration, although to a substantially
lesser degree than in normal subjects (5,11). While it has been
shown that treatment of normal children and adults with clonidine
and GHRH has resulted in significantly enhanced growth hormone
levels (9,10), it was not known whether such treatment could be
extended to obese patients given the lack of response by such
patients to most other known treatments.
SUMMARY OF THE INVENTION
It has now been discovered that obese patients may be effectively
treated by cojointly administering an alpha-2-adrenergic agonist,
such as clonidine, and a growth hormone releasing peptide, such as
GHRH, to restore or substantially enhance growth hormone release in
such patients.
DETAILED DESCRIPTION OF THE INVENTION
While obese patients, and particularly obese children, have
exhibited an impaired GH response which heretofore could not be
restored with therapies shown to be effective in enhancing GH
response in normal patients and short stature patients, a unique
and effective treatment has now been found. This treatment involves
administering cojointly to the obese patient an effective amount of
an alpha-2-adrenergic agonist and a growth hormone releasing
peptide.
The alpha-2-adrenergic agonist may be any of those which produce a
post-synaptic stimulation of the alpha-2-adrenergic pathway so as
to inhibit somatostatin release by the hypothalamus into the
hypothalamic-pituitary portal system. Alpha-2-adrenergic agonists
which may be utilized include clonidine
(2-(2,6-dichloroanilino)-2-imidazoline), guanfacine, guanabenz,
guanclofine, guanoxabenz (U.S. Pat. No. 4,910,215), and
medetomidine (U.S. Pat. No. 4,910,214). Clonidine is preferred. The
dosage is adjusted in accordance with the needs of the patient and
the result desired. Typically, clonidine is administered orally at
a dosage of about 100 to about 300 ug/m.sup.2, preferably about 150
ug/m.sup.2. It is preferably administered from 0 to about 120
minutes, most preferably about 60 minutes, prior to administering
the growth hormone releasing peptide.
The growth hormone releasing peptide which may be utilized includes
those peptides which stimulate a GH response at the GHRH level,
i.e. stimulate the pituitary somatotropes. Such peptides include
GHRH itself in its various known active forms such as GRF 1-44, GRF
1-40, GRF 1-37 and GRF 1-29. GHRH is typically administered by
injection (i.v. or s.c.), and may be advantageously delivered in a
pulsatile manner (e.g. by infusion pump). The dosage is typically
about 1 ug/kg if administered by i.v. bolus, or about 10 ug/kg
s.c.. Obviously, the dosage and frequency of administration can be
adjusted to meet the needs of the particular patient under
treatment and the desired objective.
Other growth hormone releasing peptides which can be effectively
utilized are those short chain peptides (4-11 amino acids,
preferably 5-7 amino acids) which have been recently found to
stimulate a GH response similar to GHRH. These peptides include,
but are not limited to those active peptides which are disclosed in
U.S. Pat. Nos. 4,223,019, 4,223,020, 4,223,021, 4,224,316,
4,226,857, 4,228,155, 4,228,156, 4,228,157, 4,228,158, 4,410,512,
4,410,513, 4,411,890, 4,839,344, 4,880,777, 4,880,778, WO 89/07110,
WO 89/07111 and WO 89/10933. Of the peptides disclosed in the
above-identified patents, especially preferred are peptides of the
formula:
wherein AA.sub.1 is H or Ala and AA.sub.3 is D-Trp or D-.beta.-Nal,
as well as analogs and derivatives thereof with similar
activity.
EXAMPLE
Eight prepubertal obese children (boys), aged 10 to 12.4 years, all
in good general health and taking no medication, participated in
the study with informed consent (parent and child). All had height
within normal percentiles for chronological age. Bone age was
advanced 6-24 months in all but one patient and weight was above
the 100th percentile for chronological age in all cases. The
children were tested six times at random intervals ranging from 7
to 10 days, each patient serving as his own control. Studies
commenced at 0900 h after an overnight fast and bed rest and thirty
minutes after the insertion of a nontrombogenic catheter for blood
withdrawal in a forearm vein. The study consisted of administering
clonidine (Catapresan, Boehringer Ingelheim, Spain) orally at 150
micrograms/m.sup.2 at time 0 followed by administering GHRH (GRF
1-29, Serono, Spain) as an intravenous bolus at 1 microgram/kg at
time 60 minutes. The control experiments consisted of administering
on separate occasions either clonidine at time 0 or GHRH at time 60
minutes. Blood samples for GH assays (RIA, BioMerieux, France) were
taken at 15 minute intervals for two hours. The mean intra-assay
coefficient of variation was 5.9, 4.6 and 3.9% at mean GH
concentrations of 1.5, 8 and 24 micrograms/L respectively. To avoid
inter-assay variations, all samples from a subject were run in the
same assay.
Baseline plasma GH levels were not different in the 6 study days.
Oral clonidine administration did not produce any significant
plasma GH increase except for one patient who showed a maximal GH
value of 6.5 ug/L at time 105 min. The mean amplitude of maximal GH
plasma levels following clonidine challenge was 2.9.+-.0.8
ug/L.
GHRH administration produced a slight but significant increase in
plasma GH. The mean peak plasma GH level was 9.6.+-.2 ug/L, a value
significantly higher than after clonidine challenge, which peak
appeared 45 minutes after administration. This GH response to GHRH
in obese children is significantly less than the mean GH peak of
17.1.+-.4.3 ug/L found in a control group of short children
diagnosed as having constitutional growth delay. It is also
significantly less than the reported GHRH-induced GH response in
normal children and adolescents of 25.8.+-.5.6 ug/L (9). This
confirms previous reports of impaired GHRH-induced GH response in
obese children.
Pretreatment with clonidine led to a clear and substantial GH
response to GHRH with a peak value of 27.5.+-.4.3 ug/L,
significantly higher than any other study in obese children.
Moreover, GH peaked earlier, 30 minutes after administering
GHRH.
To confirm the uniqueness of the alpha-2-adrenergic agonist in
achieving substantially enhanced GH response in obese patients
versus another known GH potentiator which operates via a different
mechanism (somatostatin inhibition via activation of cholinergic
pathway), comparative experiments were performed with galanin
(Bachem, Switzerland). Galanin (Gal) was administered alone, with
clonidine (Clo) and with GHRH by infusion as a saline solution at
50 pmol/kg/min through a Millex-GY (0.22 um, Millipore) filter at
time 55 to 120 minutes in all experiments. Also, for comparison
purposes a similar group of short stature children diagnosed as
having constitutional growth delay (CGD) were administered GHRH,
galanin plus GHRH, and clonidine plus GHRH (previous study) by the
same procedure.
The results of all the experiments are summarized in the following
Table:
TABLE ______________________________________ Patient Group Therapy
Mean Peak GH Response (.mu.g/L)
______________________________________ Obese Clo 2.9 .+-. 0.8 Gal
4.1 .+-. 1.2 Clo + Gal 5.8 .+-. 1.4 GHRH 9.6 .+-. 2 Gal + GHRH 12.6
.+-. 2.6 Clo + GHRH 27.5 .+-. 4.3 CGD GHRH 17.1 .+-. 4.3 Gal + GHRH
31.6 .+-. 4.8 Clo + GHRH 40.3 .+-. 3.9 (previous study)
______________________________________
This data is evidence of dysfunction at the level of the central
adrenergic pathways involved in GH neuroregulation. This
dysfunction is responsible for the impaired GH secretion and the
impaired GHRH-induced GH response in obese children and is
consistent with the hypothesis that there is a chronic
somatostatinergic hypertone in obesity. There also appears to be a
GHRH defect in obese patients at the hypothalamic level. The
combined treatment with clonidine and GHRH restored and enhanced
growth hormone secretion in these patients well beyond any obesity
therapy studied heretofore. Such therapy would considerably improve
the therapeutic affect of a hypocaloric diet. The superior effect
of the alpha-2-adrenergic agonists such as clonidine is believed to
result from the direct inhibition of somatostatin, unlike the
indirect inhibition that occurs with the cholinergic agonists.
REFERENCE
1. Williams, N. Engl. J. Med. 311:1403, 1984
2. Kopelman, Clin. Endocrinol. 23:87, 1985
3. Kopelman, Clin. Endocrinol. 24:157, 1986
4. Loche, Clin. Endocrinol. 27:145, 1987
5. Cordido, J. Clin. Endocrinol. Metab., 68:290, 1989
6. Ghigo, J. Endocrinol Invest. 12:99, 1989
7. Davis, J. Clin. Endocrinol. Metab. 65:1248, 1987
8. Chatterjee, J. Endocrinol. 116:R1-R2, 1988
9. Reiter, J. Pediat. Endocrinol. 3:21, 1988
10. Arce, Neuroendocrinology 52/S1/90:119, 1990, Poster 3.50 of 2nd
Int'l Cong. of Neuroendocrinology held Jun. 24-29, 1990
11. Ghigo, "Effects of the Enhancement of the Cholinergic Activity
on Growth Hormone Secretion in Children: Clinical Implications",
Recent Advances in Basic and Clinical Neuroendocrinology (eds.
Casanueva and Dieguez) pp. 241-250, 1989, Excerpta Medica,
Amsterdam
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